Ross John Baldessarini

Contributions: Research, Education and Clinical Activities

Research Contributions

Since the 1960s, Professor Baldessarini led a program of laboratory-based research in basic and preclinical neuropharmacology and behavioral psychopharmacology, as well as participating in a range of collaborative clinical research projects. His laboratory career at Harvard Medical School began in 1969, with continuous leadership of a Laboratory of Neuropsychopharmacology there and later at the then-new Mailman Research Center at McLean Hospital from 1977 to its closing in 2010. His preclinical contributions included basic studies of methylation pathways involved in the biosynthesis of potentially psychotomimetic indoleamines and other endogenous compounds. This work led to development of early biochemical assays of S-adenosyl-L-methionine (SAMe), the primary donor of methyl groups in intermediary metabolism, as well as assays of activities of enzymes that produce SAMe (L-methionine-adenosyltransferase), several monoamine methyl transferases, and levels of monoamines that can be methylated. This work established that large doses of the exogenous amino acid L-methionine (one of the rare replicated interventions that can worsen psychotic symptoms in schizophrenia patients) can increase tissue levels of SAMe, without increasing the production of methylated amines that might induce or worsen psychotic symptoms, largely as normal tissue concentrations of SAMe are already in excess of those required to sustain maximum rates of methyl transferases.

Additional studies clarified molecular requirements for transport, storage, and release of normal and abnormal monoamines in cerebral nerve terminals, including use of methods of assessing transport rates into isolated nerve terminals (“synaptosomes”) and release from superfused brain slices in physiological, oxygenated media in vitro by novel methods developed by Dr. Baldessarini. This basic work led to collaborative studies with MGH colleagues of abnormalities of monoamine metabolism in hepatic encephalopathy that supported a “false neurotransmitter” hypothesis which proposed that nerve terminals in the brain may accumulate and release physiologically in active monoamines (such as tyramine and octopamine) normally present only in trace quantities. In turn, this work led to one of the first rational and effective medical treatments for hepatic encephalopathy, based on use of parenteral nutrient solutions low in aromatic amino acids and high in neutral aliphatic amino acids that can compete for transport past the blood-brain barrier.

His early work also led to evidence that long-term pharmacological removal of monoamine transmitters, or prolonged blockade of their receptors can induce upregulation and supersensitivity of receptors, including dopamine D2 type receptors following long-term exposure to neuroleptic-antipsychotic drugs. This work led to the first plausible theory of the pathophysiology of tardive dyskinesia, formerly the most ominous adverse effect of long-term antipsychotic drug treatment. It also encouraged Dr. Baldessarini’s involvement with clinical studies of the epidemiology of tardive dyskinesia and strategies for minimizing its risk, leading to his invitation to chair the first APA task force on this topic.

More recent studies based at McLean Hospital have included extensive studies of the neuropharmacological characteristics of various types of dopamine receptors, including some of the first studies of the pharmacology of type D1 receptors and of D4 receptors. Included were some of the first studies of dopamine D2 partial-agonists (including ergolines and novel aporphines) as a potential improved antipsychotic agents with low risk of extrapyramidal neurological adverse effects. In addition, he developed orally active dopamine agonists for potential use in the treatment of Parkinson’s disease.

Other recent studies included development of novel radioligands and alkylating for the various types of dopamine receptors, as well as novel radioligands for dopamine, norepinephrine, and serotonin transporters. Some of these compounds are now commercially available as experimental tools, and others are in use as radioligands for PET and SPECT neuroimaging technologies.

Studies of the dopamine D4 receptor led to development of evidence that D4 antagonists can reduce the behavioral hyperactivity associated with a widely employed animal model of attention-deficit hyperactivity disorder (ADHD), whereas agonists worsen the condition. This discovery parallels clinical genetic evidence of an association of clinical ADHD. This work is currently being extended to studies of the neuropharmacology of animal cognitive models of attention and stopping ongoing behavior as models of important components of the cognitive deficits in ADHD.

Dr. Baldessarini also recently developed a program of research on bipolar disorder (BD) based on an international consortium of investigators, some of whom travel to McLean Hospital regularly. This work has helped to clarify a number of formerly poorly understood aspects of the natural history and improved treatment of this and other major psychiatric disorders, notably including evidence: [a] of severe iatrogenic-pharmacodynamic risks of early relapse on abrupt vs. gradual discontinuation of antidepressants, antipsychotics, and mood-stabilizing agents, including during pregnancy; [b] of superiority of lithium treatment for rapid-cycling BD; [c] strong evidence of a suicide risk-reducing effect of lithium treatment that is much stronger than for any other form of psychiatric treatment; [d] progressive worsening of BD over time (rising cycling rate) that has been reported over the past century is largely accounted for by a sampling-statistical artifact; and [e] that delay of starting long-term maintenance treatment in BD, or a higher recurrence count, does not lead to inferior clinical benefits; [e] suicidal risk is at least as high in type II as type I BD; [f] a series of studies indicating that the course and predominant morbidity in BD can be predicted quantitatively by the nature of initial illness episodes and first cycle of illness and recovery; [g] studies quantifying spontaneous and drug-associated rates of conversion of apparent unipolar depression to BD; [h] studies identifying early risk factors for later BD vs. other major psychiatric disorders.

Teaching

Professor Baldessarini developed the initial residency training program in psychopharmacology at MGH in the early 1970s, leading to development of his textbook on the topic, Chemotherapy in Psychiatry (Harvard University Press 1977, 1985, and Springer Press 2013), as well as his invitation to author the chapters on psychopharmacology for the leading textbook of general pharmacology, Goodman & Gilman’s The Pharmacological Basis of Therapeutics, through the past five editions since 1980, including the 11th edition of 2005. He has for many years led the introductory courses in psychopharmacology for PGY-II residents, as well as clinical training in clinical psychopharmacology for PGY-III residents through the MGH Psychopharmacology Clinic that he help to found in the early 1970s, as well as in a parallel clinical training program based at McLean Hospital’s outpatient services, as well as in a psychopharmacology consultation service that he directed in recent years following the semi-retirement of its founder Professor Jonathan Cole. He was one of the founders of the MGH CME program and has been a consistent contributor to CME activities on psychopharmacology and psychiatric therapeutics at MGH and McLean Hospitals and Harvard Medical School, as well as providing many lectures and short courses in theoretical and clinical psychopharmacology across the country and internationally through his frequent invitations as a visiting professor in leading centers of academic psychiatry.

He has also contributed heavily and consistently over the several decades to teaching of clinical diagnosis and therapeutics of major psychiatric disorders, including psychotic and manic-depressive disorders, initially as an attending psychiatrist and consultant on the MGH and LMHC psychiatric inpatients services, and in a similar role at McLean Hospital. He also created the Harvard Medical School Advanced Clerkship (HMS 501-M10B) at McLean Hospital for medical students, as well as participating in the redesign of the HMS Psychiatry 700 Course in Introduction to Clinical Psychiatry in the 1980s. In addition, he was the founding academic director of the Bipolar and Psychotic Disorders Program at McLean Hospital (1988–2004), and continues as a senior consultant, including regular case conferences in the successor Psychotic and Bipolar Disorders Program.

His educational activities also included regular involvement in the MGH-McLean Residency Selection and Training programs for several decades. This involvement continues to include providing special mentoring to residents with special needs as well as introducing a large number of residents as well as graduate and medical students into research careers. Since 1969, he has supervised the dissertation projects of 4 PhD candidates, as well as mentoring the research of 100 postdoctoral laboratory and clinical research trainees, as well as 65 predoctoral candidates and premedical and medical students in his laboratory.

Among the 65 undergraduate or graduate students, 5 carried out doctoral dissertation projects in the laboratory.

Among the 100 postdoctoral fellows, 26 held PhDs, usually from related but different fields from the topic of their fellowship training, and little prior interest in mental health-related neuroscience research; the others were MDs, usually with psychiatric or neurological training and strong commitment to an academic and research career; 47/100 were women, members of minority groups (mainly Hispanic or Asian), or both, as were 17/68 pre-doctoral trainees.

Seclected InvitedCourses&Lectures (N>400)

Lecturer in Biochemical Neuropharmacology and Neurophysiology, College de France, Paris, 1966